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Identification of a Putative SARS-CoV-2 Main Protease Inhibitor through In Silico Screening of Self-Designed Molecular Library.

ABSTRACT: There have been outbreaks of SARS-CoV-2 around the world for over three years, and its variants continue to evolve. This has become a major global health threat. The main protease (M^pro, also called 3CL^pro) plays a key role in viral replication and proliferation, making it an attractive drug target. Here, we have identified a novel potential inhibitor of M^pro, by applying the virtual screening of hundreds of nilotinib-structure-like compounds that we designed and synthesized. The screened compounds were assessed using SP docking, XP docking, MM-GBSA analysis, IFD docking, MD simulation, ADME/T prediction, and then an enzymatic assay in vitro. We finally identified the compound V291 as a potential SARS-CoV-2 M^pro inhibitor, with a high docking affinity and enzyme inhibitory activity. Moreover, the docking results indicate that His41 is a favorable amino acid for pi-pi interactions, while Glu166 can participate in salt-bridge formation with the protonated primary or secondary amines in the screened molecules. Thus, the compounds reported here are capable of engaging the key amino acids His41 and Glu166 in ligand-receptor interactions. A pharmacophore analysis further validates this assertion.

SUBMITTER: Liu N

PROVIDER: S-EPMC10379331 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Identification of a Putative SARS-CoV-2 Main Protease Inhibitor through In Silico Screening of Self-Designed Molecular Library.

Liu Nanxin N Yang Zeyu Z Liu Yuying Y Dang Xintao X Zhang Qingqing Q Wang Jin J Liu Xueying X Zhang Jie J Pan Xiaoyan X

International journal of molecular sciences 20230713 14

There have been outbreaks of SARS-CoV-2 around the world for over three years, and its variants continue to evolve. This has become a major global health threat. The main protease (Mpro, also called 3CLpro) plays a key role in viral replication and proliferation, making it an attractive drug target. Here, we have identified a novel potential inhibitor of Mpro, by applying the virtual screening of hundreds of nilotinib-structure-like compounds that we designed and ...[more]

PMID: 37511149

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Project description:Coronavirus (covid-19) infection is considered to be deadliest ever pandemic experienced by the human being. It has very badly affected the socio-economic health of human and stuck the scientific community to think and rethink about its complete eradication. But due to no effective treatment or unavailability of vaccine the health professional could not show any significant improvement to control the pandemic. The situation needs newer molecule, vaccine or effective treatment to control covid-19 infection. Different target in viruses has been explored and proteases enzymes were found to be therapeutically effective target for the design of potential anti-covid-19 molecule as it plays the vital role in viral replication and assembly. Structure-based drug design was employed to discover the small molecule of anti-covid-19. Here we considered the small library of naturally occurring polyphenolic compounds and molecular docking, Molecular dynamics (MD) simulations, free binding energy calculation and in-silico ADME calculations to identify the newer HITs. Based upon their score the two molecules were identified as promising candidate. The docking scores were found to be -7.643 and -7.065 for the HIT1 and HIT-2 respectively. In MD simulations study the RMSD values were found to be 4.3 Å & 4.9 Å respectively. To validate these results MM-GBSA was performed and their binding free energies were computationally determined. The prime energy values of identified HITs (-13412.45 & -13441.8 kJ/mole) were found to be very close proximity to reference molecule (-13493.05 kJ/mole). Then in-silico ADME calculations were performed to calculate the drug likeliness identified HITs. BY considering all the values comparative to reference molecule and obtained in-silico pharmacokinetic properties of identified HITs we can suggest that HIT-1 and HIT-2 would be the most promising molecules that can inhibit the main protease enzyme of covid-19. These two molecules would become the potential drug candidate for the treatment of covid-19 infections.

Dataset Information

Identification of a Putative SARS-CoV-2 Main Protease Inhibitor through In Silico Screening of Self-Designed Molecular Library.

Publications

Identification of a Putative SARS-CoV-2 Main Protease Inhibitor through In Silico Screening of Self-Designed Molecular Library.

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